The proposed research continues previously funded studies of behavioral, cellular, and molecular genetic aspects of hypothalamic-pituitary-adrenal (HPA)-axis regulation and post-stress recovery. The central hypothesis is that diminished hippocampal volume is a cause and not just an effect of stress-related psychopathology as modeled in adult female monkeys. Female animal models of stress-related depressive disorders are important because prevalence rates of depression in women are nearly two-times higher than in men. There is also a need to bridge the gap between brain imaging studies of humans with major depression and animal models that focus on cellular and molecular levels of neuroscience research. In this regard, nonhuman primates offer attractive opportunities for cross-disciplinary translational research. The studies proposed here test in monkeys the following specific predictions. Adult females with small hippocampal volumes (i.e., selected from the bottom third of a normal distribution) determined before initiation of the study will respond to repeated exposure to cycles of social isolation-induced hypercortisolism with impaired spatial memory, increased anhedonia, and HPA-axis dysregulation as compared to females with large hippocampi (i.e., top third of the distribution) exposed to cycles of social isolation, or matched female monkey controls housed continuously in pairs. In response to subsequent social stimulation after each cycle of social isolation, females with small hippocampi will show an impaired capacity for recovery. Females exposed to cycles of isolation and social stimulation will also exhibit hippocampal volume loss as compared to matched female controls housed continuously in pairs. The behavioral and neuroendocrine effects of hippocampal atrophy will be greatest in females with initially small hippocampal volumes as predicted by a threshold model described in the Research Plan. Adult females with initially small hippocampi will respond to repeated isolation and social stimulation with diminished hippocampal neurogenesis and increased glucocorticoid receptor gene expression compared to females with equally small hippocampi housed in stable pairs. These studies cross the boundaries of molecular, cellular, and behavioral neuroscience with the ultimate goal of building a foundation for improved treatments and the prevention of major depression by elucidating the relationship between hypercortisolism and hippocampal volume.